Showing papers by "Richard Bucala published in 2007"
TL;DR: Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition and displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis.
Abstract: The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G αi- and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo, Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition. © 2007 Nature Publishing Group.
1,108 citations
TL;DR: Therapeutic antagonism of MIF may be an effective approach for steroid-sparing therapies in patients with refractory autoimmune or inflammatory diseases.
Abstract: The cytokine macrophage migration inhibitory factor (MIF) occupies a unique position in physiology by its ability to directly regulate the immunosuppressive actions of glucocorticoids. We review herein the interactions between MIF and glucocorticoids within the immune system and discuss the relevance of the MIF-glucocorticoid regulatory dyad in physiology and immunopathology. Therapeutic antagonism of MIF may be an effective approach for steroid-sparing therapies in patients with refractory autoimmune or inflammatory diseases.
237 citations
TL;DR: The current understanding of MIF's role is discussed and it is highlighted as a potential link between inflammatory activation and malignant progression.
193 citations
TL;DR: Analysis of molecular mechanism regulated by CD74 in B-CLL cells shows that activation of cell-surface CD74, expressed at high levels from an early stage of the disease by its natural ligand, macrophage migration-inhibition factor (MIF), initiates a signaling cascade that contributes to tumor progression.
Abstract: Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Previous studies have shown that CLL B lymphocytes express relatively large amounts of CD74 mRNA relative to normal B cells. In the present study, we analyzed the molecular mechanism regulated by CD74 in B-CLL cells. The results presented here show that activation of cell-surface CD74, expressed at high levels from an early stage of the disease by its natural ligand, macrophage migration-inhibition factor (MIF), initiates a signaling cascade that contributes to tumor progression. This pathway induces NF-κB activation, resulting in the secretion of IL-8 which, in turn, promotes cell survival. Inhibition of this pathway leads to decreased cell survival. These findings could form the basis of unique therapeutic strategies aimed at blocking the CD74-induced, IL-8- dependent survival pathway.
179 citations
TL;DR: Direct evidence is provided for the involvement of MIF in viral pathogenesis and pharmacotherapeutic approaches targeting MIF may hold promise for the treatment of WNV encephalitis and indicates that MIF favors viral neuroinvasion by compromising the integrity of the blood-brain barrier.
Abstract: The flavivirus West Nile virus (WNV) is an emerging pathogen that causes life-threatening encephalitis in susceptible individuals. We investigated the role of the proinflammatory cytokine macrophage migration inhibitory factor (MIF), which is an upstream mediator of innate immunity, in WNV immunopathogenesis. We found that patients suffering from acute WNV infection presented with increased MIF levels in plasma and in cerebrospinal fluid. MIF expression also was induced in WNV-infected mice. Remarkably, abrogation of MIF action by 3 distinct approaches (antibody blockade, small molecule pharmacologic inhibition, and genetic deletion) rendered mice more resistant to WNV lethality. Mif(-/-) mice showed a reduced viral load and inflammatory response in the brain when compared with wild-type mice. Our results also indicate that MIF favors viral neuroinvasion by compromising the integrity of the blood-brain barrier. In conclusion, the data obtained from this study provide direct evidence for the involvement of MIF in viral pathogenesis and suggest that pharmacotherapeutic approaches targeting MIF may hold promise for the treatment of WNV encephalitis.
142 citations
TL;DR: CD44 plays a previously unrecognized role in preventing exaggerated inflammatory responses to LPS by promoting the expression of negative regulators of TLR-4 signaling.
Abstract: CD44 is a transmembrane adhesion molecule and hemopoietic CD44 has an essential role in hyaluronan clearance and resolution of noninfectious lung injury. In this study, we examined the role of CD44 in acute pulmonary inflammation and in the regulation of LPS-TLR signaling. Following intratracheally LPS treatment, CD44−/− mice demonstrated an exaggerated inflammatory response characterized by increased inflammatory cell recruitment, elevated chemokine expression in bronchoalveolar lavage fluid, and a marked increase in NF-κB DNA-binding activity in lung tissue in vivo and in macrophages in vitro. Furthermore, CD44−/− mice were more susceptible to LPS-induced shock. Reconstitution of hemopoietic CD44 reversed the inflammatory phenotype. We further found that the induction of the negative regulators of TLR signaling IL-1R-associated kinase-M, Toll-interacting protein, and A20 by intratracheal LPS in vivo and in macrophages in vitro was significantly reduced in CD44−/− mice. Collectively, these data suggest CD44 plays a previously unrecognized role in preventing exaggerated inflammatory responses to LPS by promoting the expression of negative regulators of TLR-4 signaling.
129 citations
TL;DR: An important role for MIF in host glucose metabolism during sepsis is support by investigating the glycemic responses of endotoxemic mice genetically deficient in MIF, which exhibits normal blood glucose and lactate responses following the administration of endotoxin.
Abstract: Inflammation provokes significant abnormalities in host metabolism that result from the systemic release of cytokines. An early response of the host is hyperglycemia and resistance to the action of insulin, which progresses over time to increased glucose uptake in peripheral tissue. Although the cytokine TNF-α has been shown to exert certain catabolic effects, recent studies suggest that the metabolic actions of TNF-α occur by the downstream regulation of additional mediators, such as macrophage migration inhibitory factor (MIF). We investigated the glycemic responses of endotoxemic mice genetically deficient in MIF (MIF −/− ). In contrast to wild-type mice, MIF −/− mice exhibit normal blood glucose and lactate responses following the administration of endotoxin, or TNF-α. MIF −/− mice also show markedly increased glucose uptake into white adipose tissue in vivo in the endotoxemic state. Treatment of adipocytes with MIF, or anti-MIF mAb, modulates insulin-mediated glucose transport and insulin receptor signal transduction; these effects include the phosphorylation of insulin receptor substrate-1, its association with the p85 regulatory subunit of PI3K, and the downstream phosphorylation of Akt. Genetic MIF deficiency also promotes adipogenesis, which is in accord with a downstream role for MIF in the action of TNF-α. These studies support an important role for MIF in host glucose metabolism during sepsis.
109 citations
TL;DR: AceMIF as mentioned in this paper is a recombinant version of the human macrophage migration inhibitory factor (MIF), which has been shown to selectively inhibit the hookworm cytokine as a means of reducing parasite survival.
97 citations
TL;DR: Individuals with −173G/C, −173C/C and −794 7-CATT MIF genotypes have an increased incidence of CaP and these genotypes may serve as an independent marker for cancer recurrence.
Abstract: Recurrent or persistent inflammation has emerged as an important factor in cancer development. Overexpression of macrophage migration inhibitory factor (MIF), an upstream regulator of innate immunity with pleiotropic effects on cell proliferation, has been implicated in prostate cancer (CaP). Two polymorphisms in the promoter of the MIF gene (-173G to C transition and seven copies of the -794 CATT repeat) are associated with increased MIF expression in vivo and poor prognosis in autoimmune diseases. We conducted a retrospective analysis of 131 CaP patients and 128 controls from a group of Veterans' Administration patients undergoing routine prostate-specific antigen screening. Patients with CaP were enrolled regardless of treatment. Inclusion criteria for the control group were absence of documented diagnosis of cancer and/or chronic inflammation within patient computerized records. Logistic regression demonstrated a significant association between CaP and the -173G/C, the -173C/C and the -794 7-CATT MIF polymorphisms (P<0.001). Patients with the -794 7-CATT allele had an increased risk of CaP recurrence at 5 years. Individuals with -173G/C, -173C/C and -794 7-CATT MIF genotypes have an increased incidence of CaP and these genotypes may serve as an independent marker for cancer recurrence.
89 citations
TL;DR: The CD74/NF-kappaB/TAp63 axis defines a novel antiapoptotic pathway in mature B cells, resulting in the shaping of both the B-cell repertoire and the immune response.
81 citations
TL;DR: Estrogen decreases while progesterone increases MIF production in the female rat colon, and changes in basal MIF contents may affect colon susceptibility to inflammation, by modulating TNF-alpha and IL-1beta production during early stages of colitis.
Journal Article•
TL;DR: SF MIF may reflect the clinical activity in patients with RA, and rhMIF induces the angiogenic factors in RA synovial fibroblasts, and these results suggest that Mif may be an important cytokine in the perpetuation of theAngiogenic and inflammatory processes in Patients with RA.
Abstract: OBJECTIVE: To investigate the relationship between macrophage migration inhibitory factor (MIF) levels and clinical measures in rheumatoid arthritis (RA), and the potential for regulation of angiogenesis in RA. METHODS: Serum and synovial fluid (SF) levels of MIF and vascular endothelial growth factor (VEGF) in patients with RA were determined by sandwich ELISA, and the relationships among MIF, VEGF, and RA clinical measures were analyzed. RA synovial fibroblasts were cultured with recombinant human MIF (rhMIF) and the production of VEGF and interleukin 8 (IL-8) were measured in the conditioned media. The angiogenic effect of MIF was examined using established measures of angiogenesis in vitro. RESULTS: Erythrocyte sedimentation rate, C-reactive protein, and the daily dosage of oral prednisolone were correlated with SF levels of MIF. The SF levels of MIF were found to be higher in patients with bony erosion than in those without (69.2 +/- 11.4 ng/ml vs 44.0 +/- 6.2 ng/ml; p = 0.045). MIF levels had good correlation with VEGF levels (r = 0.52, p
TL;DR: It is shown that Toll-like receptor (TLR) signaling influences the development of lethal CM in P. berghei ANKA-infected mice through modulation of cytokine production and T(reg) cell numbers.
Abstract: InfectionwithPlasmodiumbergheiANKAisawell-establishedmodelofhumancerebralmalaria(CM).Weshow herein that Toll-like receptor (TLR) signaling influences the development of lethal CM in P. berghei ANKA‐ infected mice. Modulation of outcome was dependent on genetic background, such that deletion of myeloid differentiation factor (MyD) 88 on the susceptible C57BL/6 background resulted in resistance to CM, whereas deletion of MyD88 on the resistant BALB/c background led to increased mortality. Our data show that MyD88 influenced the production of T helper‐polarizing cytokines, including interferon (IFN)‐, interleukin (IL)‐4, and IL-17, as well as the total number of Foxp3 regulatory T (Treg) cells in a manner dependent on host genetic background.Inaddition,mRNAlevelsofIFN-,CXCL10,andCXCL9werestronglyup-regulatedinthebrainsof susceptible wild-type but not MyD88 / infected mice. These results suggest that TLR signaling and host genetic background influences the pathogenesis of CM via modulation of cytokine production and Tregcell numbers. Plasmodium species, the causative agents of malaria, in
TL;DR: The aim of this study was to investigate the signaling mechanism by which MIF induces MMP-9 expression and activation in a murine macrophage line (RAW264.7), and the functional role of mitogen-activated protein kinase kinase (MEK)-ERK MAP kinase in MIF-induced M MP- 9 expression was confirmed.
Abstract: We have shown previously that macrophage migration inhibitory factor (MIF) may play a role in the destabilization of atherosclerotic plaques by activating matrix metalloproteinase protein-9 (MMP-9). The aim of this study is to investigate the signaling mechanism by which MIF induces MMP-9 expression and activation in a murine macrophage line (RAW264.7). MIF was able to activate extracellular signal-regulated kinase 1/2 (ERK1/2), to a less extent JNK, but not p38 mitogen-activated protein (MAP), MAP kinase to induce MMP9 mRNA and protein expression in RAW264.7 murine macrophages. This was confirmed by the findings that addition of an ERK MAP kinase inhibitor (PD98059) but not a p38 inhibitor (SB203589) abolished MIF-induced MMP-9 expression and activation, whereas addition of a JNK inhibitor (SP600125) produced a partially inhibitory effect. The functional role of mitogen-activated protein kinase kinase (MEK)-ERK MAP kinase in MIF-induced MMP-9 expression was further confirmed by overexpressing dominant negative MEK (DN-MEK) and DN-ERK MAP kinases. Interestingly, constitutive expression of a wild-type (WT)-MEK alone was also capable of inducing a low, but significant MMP-9 mRNA and protein expression but did not cause a further increase in MMP-9 in response to MIF. MIF activates the MEK-ERK MAP kinase pathway to induce MMP-9 expression by murine macrophages. Activation of this pathway is necessary for MMP-9 expression and activation in response to MIF stimulation.
TL;DR: Muscle invasive bladder cancer with increased stromal vascularity was associated with increased MIF mRNA levels and nuclear redistribution, suggesting that MIF may play a role in the progression tovasive bladder cancer.
Abstract: Inflammatory cytokines may promote tumorigenesis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with regulatory properties over tumor suppressor proteins involved in bladder cancer. We studied the development of bladder cancer in wild type (WT) and MIF knockout (KO) mice given N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), a known carcinogen, to determine the role of MIF in bladder cancer initiation and progression. 5-month old male C57Bl/6 MIF WT and KO mice were treated with and without BBN. Animals were sacrificed at intervals up to 23 weeks of treatment. Bladder tumor stage and grade were evaluated by H&E. Immunohistochemical (IHC) analysis was performed for MIF and platelet/endothelial cell adhesion molecule 1 (PECAM-1), a measure of vascularization. MIF mRNA was analyzed by quantitative real-time polymerase chain reaction. Poorly differentiated carcinoma developed in all BBN treated mice by week 20. MIF WT animals developed T2 disease, while KO animals developed only T1 disease. MIF IHC revealed predominantly urothelial cytoplasmic staining in the WT control animals and a shift toward nuclear staining in WT BBN treated animals. MIF mRNA levels were 3-fold higher in BBN treated animals relative to controls when invasive cancer was present. PECAM-1 staining revealed significantly more stromal vessels in the tumors in WT animals when compared to KOs. Muscle invasive bladder cancer with increased stromal vascularity was associated with increased MIF mRNA levels and nuclear redistribution. Consistently lower stage tumors were seen in MIF KO compared to WT mice. These data suggest that MIF may play a role in the progression to invasive bladder cancer.
TL;DR: Fibrocytes circulate in the peripheral blood, produce collagen and other matrix proteins, and express cell surface markers indicative of a hematopoetic origin distinguishing them from fibroblasts, which are first identified in 1994 in a model system of wound repair.
Abstract: Fibrocytes circulate in the peripheral blood, produce collagen and other matrix proteins, and express cell surface markers indicative of a hematopoetic origin distinguishing them from fibroblasts. Circulating fibrocytes were first identified in 1994 in a model system of wound repair, and defined by their growth characteristics and unique surface phenotype. The methods currently employed for the isolation, growth, and characterization of peripheral blood fibrocytes rely on the entry of "fibroblast-like" cells into wound chambers, or the derivation of "fibroblast-like" cells from the buffy coat of peripheral blood obtained from different mammalian species. In this protocol, we culture fibrocytes from the mononuclear cells of peripheral blood and harvest the cultured cells for flow cytometry analysis.
TL;DR: Intracellular F2,6BP levels in peripheral blood mononuclear cells from normal control subjects were significantly lower than age-matched diabetic subjects and a significant positive correlation between intracellular F 2,6 BP levels and long term glycemic control, as assessed by HbA1c was observed.
Abstract: Fructose 2,6-bisphosphate (F2,6BP) is a powerful allosteric activator of 6-phosphofructo-1-kinase, which is the rate-limiting enzyme for glycolysis. Mitogenic stimulation of lymphocytes is related to an enhanced rate of glucose utilization and F2,6BP mediated activation of glycolysis. To determine the effect of hyperglycemia on intracellular glycolysis of lymphocytes, we measured intracellular F2,6BP content in peripheral blood mononuclear cells obtained from patients with diabetes and normal subjects. A total of 62 subjects participated in the present study. Venous blood samples were collected and peripheral blood mononuclear cells were separated by Ficoll gradients. Intracellular F2,6BP levels in peripheral blood mononuclear cells from normal control subjects were significantly lower than age-matched diabetic subjects. We observed a significant positive correlation between intracellular F2,6BP levels and long term glycemic control, as assessed by HbA1c. These data suggest that hyperglycemia increases intracellular F2,6BP in immune cells. These findings may help to clarify the impaired function in immune cells in patients with diabetes.
Patent•
05 Jul 2007TL;DR: In this paper, a method for diagnosing bladder disease and/or severity comprising screening for a MIF gene or MIF receptor gene polymporhism or expression level.
Abstract: The invention relates generally to methods for treating, and/or preventing bladder disorders. In certain embodiments the invention comprises methods for the treatment and/or prevention of a bladder disorder comprising administering an effective amount of a therapeutic agent that decreases the expression, release or biological activity of macrophage migration inhibition factor (MIF) to a subject in need thereof. In other aspects the invention relates to a method for diagnosing bladder disease and/or bladder disease severity comprising screening for a MIF gene or MIF receptor gene polymporhism or expression level.
Patent•
31 Oct 2007
TL;DR: Methods and compositions for using the MHC class II invariant chain polypeptide, Ii (also known as CD74), as a receptor for macrophage migration inhibitory factor (MIF), are disclosed in this article.
Abstract: Methods and compositions for using the MHC class II invariant chain polypeptide, Ii (also known as CD74), as a receptor for macrophage migration inhibitory factor (MIF), are disclosed. These include methods and compositions for using this receptor, as well as agonists and antagonists of MIF which bind to this receptor, or which otherwise modulate the interaction of MIF with CD74 or the consequences of such interaction, in treatment of conditions characterized by locally or systemically altered MIF levels, particularly inflammatory conditions and cancer.